Local Anaesthetic Agents

Action:

Reversible depression of nerve conductance along central and peripheral pathways. The
agents diffuse through the lipid cell membrane in the unionised state and interact with a
specific receptor-like site on the sodium channel in the ionised state:

The Modulated receptor hypothesis:
The affinity of the receptor is modulated by the channel state (open, inactivated or
resting). The selective binding to the sodium channels in the inactivated-closed state
will prevent the channels from changing to the open or resting state and so prevent nerve
impulses. The local anaesthetic molecules can only gain access to receptors when the
channel is open, when resting some of the drug detaches from the receptor, if the channel
is then re-opened an increase in the amount of local anaesthetic occurs leading to a
frequency-dependant block - a block that is dependant on the characteristic frequency of
activity of the nerve as well as on its anatomical properties (diameter, mylination)

The Guarded receptor hypothesis:
The affinity is constantly high, but access of the local anaesthetic to the receptor is
guarded by channel "gates".

Local anaesthetics prevent the opening of the sodium channels and delay the rate of
conduction of action potentials, without changing the resting membrane potential. They can
also block certain potasium channels, further modifying the conduction of action
potentials. They do inhibit the action of phospholipase A 2 and interfere with
prostoglandin synthesis.

Sensory physiology

The sense organs for mechanical stimulation, temperature, proprioception and pain
transmit information via various types of primary afferent nerve fibres to the dorsal horn
of the spinal cord. Propinospinal neurones, which are totally confined to the spinal cord,
transmit the information through the dorsal horn. Ascending neurones then take the
information for interpretation to the appropriate supraspinal destination. A descending
pathway from the midbrain modulates the sensory input at different points in the spinal
cord, ending at the dorsal horn of the spinal cord.

The primary afferent nerve fibres have been divided into seven different groups
depending on their function.

Aa - Somatic motor and proprioception

Ab - Touch and pressure - circumvent the dorsal horn by
giving off collaterals that ascend in the posterior columns

Preferential blockade of a nerve requires a minimal length of fibre exposed to an
adequate concentration (Cm) of local anaesthetic. The blocking of three sequential nodes
of Ranvier is always sufficient. As thick fibers have an increased distance between nodes
of Ranvier this explains the onset of fiber blockade

And the differential blockade seen with different concentrations of local anaesthetics
is explained by the Cm (c. f. MAC) which is in itself influenced by nerve fiber diameter,
tissue pH and frequency of nerve firing.

Local anaesthetics are a safe and effective and highly desirable means for achieving
analgesia. However, if you use them enough, despite your best precautions, you will
encounter toxicity. If you are not prepared to deal with it, this toxicity may result in
serious harm or death. The first step is to recognise toxicity, which takes two major
forms:

Neurotoxicity

Cardiotoxicity

Lignocaine, bupivacaine and ropivacaine are all more likely to cause neurotoxicity than
cardiac toxicity. This relative risk has been called the cc:cns ratio. The dose
in (mg/Kg) that cause cardiovascular collapse vs the dose in (mg/Kg) that cause
central nervous system collapse is the CC/CNS ratio. It has
been estimated that 7 times the dose of lignocaine that caused seizures will cause a
cardiac arrest.

Neurotoxicity often starts with a change in mentation, followed by
perioral paraesthesia, a feeling that the subject's whole body is flushing, tinnitus and
other neurological symptoms culminating in generalised seizures.

The initial neurological manifestation is often missed by the incautious doctor, as it
may manifest as:

The patient becomes garrulous and starts talking rubbish

The patient goes absolutely quiet

The first and most important rule of local anaesthesia is thus clear: Keep the patient
talking at all times!

Cardiotoxicity This is a rightly feared consequence of high blood levels
of local anaesthetic.

It starts with peripheral arteriolar and venous dilatation, then

Decreased myocardial contractility (inhibition of Ca 2+
channels).

A decrease in cardiac rate.

Quinidine like action on the action potential with an

increase in the refractory period,

an increased firing threshold,

increased conduction time.

Bradycardia with a long p-r interval, widened QRS complex and an
increased Q-Tc leading on to any form of dysrhythmias (blocks, re-entry, ventricular
ectopics)

Management of toxicity

Most important is to be prepared to resuscitate the patient, and know your 'ABC'.
Prolonged cardiopulmonary resuscitation may be required, especially with bupivacaine which
has a longer half-life than lignocaine.

Prevent toxicity

Know your toxic doses and keep within the limits

Know how to preform the techniques, be meticulous at all times

Despite the best will in the world, toxic reactions will still occur

Get help now!

Secure and maintain airway and oxygenation - wether you use a mask or
endotracheal tube, ventilatory support as necessary.

Ensure intravenous access.

Control convulsions - Thiopentone or a short or long acting
benzodiazepine

Lemicoline (an active enantiomer of cromakalim) 0.03 mg/Kg. It is a Na +
K + ATPase activator. It restores Vmax and the maximal negative potential
of the cell. It shortens ventricular repolarisation and decreases the
refractory period, thereby reducing the Q-Tc. It causes vasodilatation and will
worsen the hypotension. This drug has been shown to reverse the electrophysical changes in
the heart caused by bupivicaine, but it does not ameliorate the haemodynamic alterations
from bupivicaine toxicity.

Allergy

Allergy to amide local anaesthetics is extremely uncommon, if it exists. Ester local
anaesthetics, which are infrequently used, are much more often associated with allergy
because they are metabolised to para-amino benzoic acid, which acts as a hapten.

Toxicity related to additives

Multi-use vials

These are a cost-saving abomination. They usually contain methyl paraben as a
preservative, which is neurotoxic. There are thus several good reasons why you should
never use a multi-use vial, including:

Bacterial contamination is common (despite the preservative);

Adverse reactions may occur to methyl paraben;

Severe neurotoxicity has been reported when methyl paraben has been given epidurally or
spinally.

Mixtures

Mistrust doctors who make complex concoctions, especially for epidural or spinal use. Next
time you have the opportunity, check the pH of dextrose (a common additive) - you will
find it to be surprisingly acidic. This, if added to carefully pH-adjusted solutions like
lignocaine or marcaine, will totally muck up the pH balance.

Neurotoxicity

Preservative in the local anaesthetic - Methylparaben, Sodium bisulfite,

High concentrations in close proximity to the nerve root (spinal or epidural) for a long
period of time.

5% spinal lignocaine

Transient Radicular Irritation : Is it a manifestation of nerve
damage?

Decreasing latency and prolongation of action of the local anaesthetic
agent

Time release preparations decrease the rate of release and increase the
local availability of the local anaesthetic preparationsBiodegradable polyanhydride
polymers for regional blockadeLipid depot in neuraxial blockade using
iophendylateLiposomal encapsulation with egg yolk phosphatidyl choline and cholesterol in
neuraxial blockade